title: Positive and negative design for nonconsensus protein-DNA binding affinity in the vicinity of functional binding sites.
abstract: Recent experiments provide an unprecedented view of protein-DNA binding in yeast and human genomes at single-nucleotide resolution. These measurements, performed over large cell populations, show quite generally that sequence-specific transcription regulators with well-defined protein-DNA consensus motifs bind only a fraction among all consensus motifs present in the genome. Alternatively, proteins in vivo often bind DNA regions lacking known consensus sequences. The rules determining whether a consensus motif is functional remain incompletely understood. Here we predict that genomic background surrounding specific protein-DNA binding motifs statistically modulates the binding of sequence-specific transcription regulators to these motifs. In particular, we show that nonconsensus protein-DNA binding in yeast is statistically enhanced, on average, around functional Reb1 motifs that are bound as compared to nonfunctional Reb1 motifs that are unbound. The landscape of nonconsensus protein-DNA binding around functional CTCF motifs in human demonstrates a more complex behavior. In particular, human genomic regions characterized by the highest CTCF occupancy, show statistically reduced level of nonconsensus protein-DNA binding. Our findings suggest that nonconsensus protein-DNA binding is fine-tuned around functional binding sites using a variety of design strategies.
authors.affiliation: Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Afek
authors.forename: David B
authors.initials: DB
authors.lastname: Lukatsky
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D059372:Nucleotide Motifs; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004268:DNA-Binding Proteins; C065681:REB1 protein, S cerevisiae; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D004247:DNA